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Recent Advances in Malaria Genomics and Epigenomics Sebastian Kirchner, B

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Recent Advances in Malaria Genomics and Epigenomics Sebastian Kirchner, B Kirchner et al. Genome Medicine (2016) 8:92 DOI 10.1186/s13073-016-0343-7 REVIEW Open Access Recent advances in malaria genomics and epigenomics Sebastian Kirchner, B. Joanne Power and Andrew P. Waters* Abstract Malaria continues to impose a significant disease burden on low- and middle-income countries in the tropics. However, revolutionary progress over the last 3 years in nucleic acid sequencing, reverse genetics, and post-genome analyses has generated step changes in our understanding of malaria parasite (Plasmodium spp.) biology and its interactions with its host and vector. Driven by the availability of vast amounts of genome sequence data from Plasmodium species strains, relevant human populations of different ethnicities, and mosquito vectors, researchers can consider any biological component of the malarial process in isolation or in the interactive setting that is infection. In particular, considerable progress has been made in the area of population genomics, with Plasmodium falciparum serving as a highly relevant model. Such studies have demonstrated that genome evolution under strong selective pressure can be detected. These data, combined with reverse genetics, have enabled the identification of the region of the P. falciparum genome that is under selective pressure and the confirmation of the functionality of the mutations in the kelch13 gene that accompany resistance to the major frontline antimalarial, artemisinin. Furthermore, the central role of epigenetic regulation of gene expression and antigenic variation and developmental fate in P. falciparum is becoming ever clearer. This review summarizes recent exciting discoveries that genome technologies have enabled in malaria research and highlights some of their applications to healthcare. The knowledge gained will help to develop surveillance approaches for the emergence or spread of drug resistance and to identify new targets for the development of antimalarial drugs and perhaps vaccines. Background to provide new avenues for therapeutic or prophylac- Malaria, caused by unicellular protozoan Plasmodium tic development based upon biological insights such spp. parasites, is an ancient disease and remains a as the identification of new drug targets and vaccine major threat to human health and wellbeing. Five candidates. species of Plasmodium are currently recognized as The landmark of the completion of the genome causing human malaria, of which the most lethal is sequence of a laboratory strain of Pf was achieved over P. falciparum (Pf). In 2015, the World Health a decade ago [2] (Fig. 1). This has since been accom- Organization estimated that the maximal annual bur- panied, thanks to plummeting costs and advances in den imposed by malaria, whilst decreasing, still stands next-generation sequencing (NGS) technologies, by the at 214 million (range 149–303 million) cases that whole-genome sequencing (WGS) of a wide range of result in 438,000 (range 236,000–623,000) deaths [1]. species representing all the major clades of the genus, Drug resistance to frontline antimalarials continues to although the genomes of all known human infectious arise and spread, exacerbated by slow progress in the Plasmodium species remain to be sequenced [3]. How- introduction of alternatives. Properly efficacious vac- ever, the combination of NGS and WGS has enabled cines remain a hope, not a likelihood. Against this the development of innovative large-scale genomic background, genome-based research on malaria seeks studies, for example, for genomic epidemiology [4]. Such population genomics, fueled by collaborative * Correspondence: [email protected] consortia (for example, the Malaria Genomic Epidemi- Wellcome Trust Centre for Molecular Parasitology, Institute of Infection, ology Network (MalariaGEN; http://www.malariagen.net), Immunity and Inflammation, College of Medical Veterinary & Life Sciences, University of Glasgow, Glasgow G12 8TA, UK have allowed the dynamics of global and local population © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Kirchner et al. Genome Medicine (2016) 8:92 Page 2 of 17 structures to be assessed and adaptive change in parasite The African Genome Variation Project recognizes the genomes to be monitored in response to threats, such significant diversity of ethnicities and, therefore, geno- as artemisinin (ART). This is especially true for single- typesand,throughWGS,imputation,andSNP nucleotide polymorphisms (SNPs), and while other mapping, seeks to build a database through which aspects of genome variation (such as indels and copy disease incidence and outcome can be reliably associ- number variation) might currently lag behind, the ated with haplotypes [7]. Already, such wider analyses gaps in the database are known and are firmly in the have confirmed SNP associations with five well-known traits, sights of researchers. including hemoglobinopathies and glucose-6-phosphate The template Plasmodium genomes have provided the dehydrogenase (G6PD) deficiency, but have refuted 22 substrate for the application of an explosion of other others that had been linked by smaller-scale studies [8]. This post-genome survey technologies that have been largely study also showed opposing effects of G6PD on different exclusively applied to Pf, such as transcriptomics, prote- fatal consequences of malaria infection, revealing a hitherto omics, metabolomics, and lipidomics, and that map the unsuspected complexity of associations. Ongoing analyses general and stage-specific characteristics of malaria para- have revealed new, although unsurprising, examples sites. These data are warehoused in expensive but critical of haplotypes of loci associated with protection from community web sites such as PlasmoDB (http://www.Plas severe malaria, such as the glycophorin locus on human modb.org). This in turn has been exploited by ever chromosome 4 [8, 9]. improving forward and reverse genetic capabilities to assign function to genes, steadily reducing the >60 % of Vector genomics genes of unknown function that were originally catalogued In Africa, malaria is mainly transmitted by female [2]. Advances that will be highlighted in this review Anopheles gambiae (Ag) mosquitoes. Approaches to include: the unraveling of the molecular mechanisms of understanding the role of Ag mosquito genomics in parasite resistance to ART; the functional identifica- malaria transmission have been similar to those of the tion of some of the histone-modifying enzymes that African Genome Variation Project. Thus, the Ag1000G write the epigenetic code (such as Pf histone deacety- project (https://www.malariagen.net/projects/ag1000g) lase 2 (PfHDA2)) and the proteins that read it (such involves 35 working groups that have sampled Ag mosqui- as Pf heterochromatin protein 1 (PfHP1)) that, with tos from 13 malaria endemic countries and that aim to others (such as RNaseII), play a significant role in the establish the levels of Ag genome diversity, establish popu- regulation of antigenic variation and commitment to lation structures, and link these to the ecology of disease sexual development. transmission. The Anopheles vector genome is very Furthermore, the genomes of the host and of a grow- dynamic. Comparative vector genomics has revealed rapid ing number of mosquito vectors have been characterized gene gain and loss compared with Drosophila and signifi- in both increasing number and depth, permitting meta- cant intragenus diversity and mixing in genes involved analyses of these genomes in combination with Plasmo- in both insecticide resistance and antimalarial immun- dium infection. These studies have revealed important ity [10, 11]. The nature and extent of such diversity loci associated with resistance to the malaria parasite in precludes the application of classic GWAS approaches the host and vector, respectively [5, 6], and indicate the and a novel approach of phenotype-driven, pooled se- genomic hotspots in the genetic arms race that malaria quencing coupled with linkage mapping in carefully has stimulated. selected founder colonies has been used to map vec- We also review the recent advances in this very active tor phenotypes. This study recently revealed TOLL11 area of malaria genomics and control of gene expression as a gene that protects African mosquitoes against Pf and emphasize any benefits that these advances may infection [6]. have for the development of therapies and interventions (Table 1). Parasite genomics Full genome sequences are now available for many Human genomics strains of Pf [2], Plasmodium vivax [12], and Plasmo- The infrastructure required to effectively collect, collate, dium knowlesi [13] among the human infectious and analyze large genomes for epidemiological studies parasites. Primate and rodent infectious species that are (that is, genome-wide association studies (GWAS)) is so frequently used as model parasites have also been costly that it is best achieved in consortia. These can sequenced and include Plasmodium berghei
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